An indole diketopiperazine alkaloid and a bisabolane sesquiterpenoid with unprecedented skeletons from Aspergillus fumigatus.

Fumitryprostatin A (1), the first example of an indole diketopiperazine alkaloid with a tricyclic 5/6/5 skeleton characterized by a dipyrrolo[1,2-a:1',2'-d]pyrazine-5,10-dione ring system decorated with a prenylated indole moiety, and fuminoid A (2), a sesquiterpenoid with a bicyclo[3.2.1]octane ring featuring a novel carbon skeleton via the transformation of the methyl, were isolated from the fungus Aspergillus fumigatus along with six known diketopiperazine alkaloids. The structure with the absolute configuration of 1 was determined based on spectroscopic analyses and X-ray crystallographic analysis, while the configuration of 2 was assigned tentatively by 13C NMR data with DP4+ probability analyses and ECD calculations. A plausible biosynthetic pathway for 1 was proposed starting from L-Trp and L-Pro via normal indole diketopiperazine. Compound 1 exhibited moderate cytotoxic activity with an IC50 value of 14.6 µM, while compound 8 exhibited moderate immunosuppressive activity in vitro.

Two Pairs of New Bisabolane-Type Sesquiterpenoids from Aspergillus sydowii.

Two pairs of new bisabolane-type sesquiterpenoids, (+)-aspersydowin A (7S) [(+)-1], (-)-aspersydowin A (7R) [(-)-1], (+)-aspersydowin B (7S,11S) [(+)-2], (-)-aspersydowin B (7R,11R) [(-)-2], along with six known compounds (1-8) were isolated from the fungus Aspergillus sydowii. Compounds 1 and 2 are enantiomers resolved by the Chiralpak IC, using a hexane- propan-2-ol mobile phase. The structure of 1 and 2 with absolute configuration were assigned tentatively by 1D (1 H, 13 C, and DEPT) & 2D (HSQC, 1 H-1 H COSY, HMBC, and NOESY) NMR data analyses and ECD calculations. Compounds 1-8 were screened for the biological activities in vitro. The results showed that compounds 3, 4 and 8 exhibited immunosuppressive activities with IC50 values of 10.9, 17.6 and 13.4 µM, respectively.

A Novel Paclitaxel Derivative for Triple-Negative Breast Cancer Chemotherapy.

Paclitaxel-triethylenetetramine hexaacetic acid conjugate (PTX-TTHA), a novel semi-synthetic taxane, is designed to improve the water solubility and cosolvent toxicity of paclitaxel in several aminopolycarboxylic acid groups. In this study, the in vitro and in vivo antitumor effects and mechanisms of PTX-TTHA against triple-negative breast cancer (TNBC) and its intravenous toxicity were evaluated. Results showed the water solubility of PTX-TTHA was greater than 5 mg/mL, which was about 7140-fold higher than that of paclitaxel (<0.7 µg/mL). PTX-TTHA (10-105 nmol/L) could significantly inhibit breast cancer proliferation and induce apoptosis by stabilizing microtubules and arresting the cell cycle in the G2/M phase in vitro, with its therapeutic effect and mechanism similar to paclitaxel. However, when the MDA-MB-231 cell-derived xenograft (CDX) tumor model received PTX-TTHA (13.73 mg/kg) treatment once every 3 days for 21 days, the tumor inhibition rate was up to 77.32%. Furthermore, PTX-TTHA could inhibit tumor proliferation by downregulating Ki-67, and induce apoptosis by increasing pro-apoptotic proteins (Bax, cleaved caspase-3) and TdT-mediated dUTP nick end labeling (TUNEL) positive apoptotic cells, and reducing anti-apoptotic protein (Bcl-2). Moreover, PTX-TTHA demonstrated no sign of acute toxicity on vital organs, hematological, and biochemical parameters at the limit dose (138.6 mg/kg, i.v.). Our study indicated that PTX-TTHA showed better water solubility than paclitaxel, as well as comparable in vitro and in vivo antitumor activity in TNBC models. In addition, the antitumor mechanism of PTX-TTHA was related to microtubule regulation and apoptosis signaling pathway activation.

Methoxypolyethylene Glycol-Substituted Zinc Phthalocyanines for Multiple Tumor-Selective Fluorescence Imaging and Photodynamic Therapy.

Highly tumor-tissue-selective drugs are a prerequisite for accurate diagnosis and efficient photodynamic therapy (PDT) of tumors, but the currently used fluorescent dyes and photosensitizers generally lack the ability for high accumulation and precise localization in tumor tissues. Here we report that monomethoxy polyethylene glycol (MPEG)-modified zinc phthalocyanine (ZnPc) can be selectively accumulated in multiple tumor tissues, and that the selectivity is controlled by the chain length of MPEG. MPEG-monosubstituted ZnPcs with different chain lengths were synthesized, among which the shorter chain (mw < 2k)-modified ZnPc did not show tumor tissue selectivity, while MPEG2k-5k-substituted ZnPc could be rapidly and selectively accumulated in H22 tumor tissues in mice after intravenous injection. Especially, MPEG4k-Pc showed the best tumor tissue selectivity with a tumor/liver (T/L) ratio of 1.7-2.2 in HepG2, MDA-MB231, AGS, and HT-29 tumor-bearing mice. It also exhibited potent photodynamic therapy effects after one PDT treatment, and tumor growth was significantly inhibited in H22-bearing mice with an inhibition rate over 98% and no obvious toxicity. Consequently, MPEG-modified ZnPc could serve as a potential platform for selective fluorescence imaging and photodynamic therapy of multiple tumors.

Design, synthesis and anticancer activity of matrine-1H-1,2,3-triazole-chalcone conjugates.

A series of novel matrine-1H-1,2,3-triazole-chalcone conjugates was synthesized and their anticancer activity against A549, Bel-7402, Hela, and MCF-7 cancer cells was evaluated. Most of the conjugates displayed higher potency than their components. Compounds 6h and 6i exhibited more potent anticancer activity than 5-fluorouracil against the four tested human cancer cell lines and lower cytotoxicity to NIH3T3 normal cells. Flow cytometry tests demonstrated that compound 6h could induce apoptosis of A549 cells in a concentration-dependent manner. Moreover, 6h could efficiently suppress human tumor growth in mouse xenograft model without causing obvious toxicities.

Silicon does not mitigate cell death in cultured tobacco BY-2 cells subjected to salinity without ethylene emission.

KEY MESSAGE: Silicon induces cell death when ethylene is suppressed in cultured tobacco BY-2 cells. There is a crosstalk between Si and ethylene signaling. Silicon (Si) is beneficial for plant growth. It alleviates both biotic and abiotic stresses in plants. How Si works in plants is still mysterious. This study investigates the mechanism of Si-induced cell death in tobacco BY-2 cell cultures when ethylene is suppressed. Results showed that K2SiO3 alleviated the damage of NaCl stress. Si treatment rapidly increased ethylene emission and the expression of ethylene biosynthesis genes. Treatments with Si + Ag and Si + aminooxyacetic acid (AOA, ethylene biosynthesis inhibitor) reduced the cell growth and increased cell damage. The treatment with Si + Ag induced hydrogen peroxide (H2O2) generation and ultimately cell death. Some nucleus of BY-2 cells treated with Si + Ag appeared TUNEL positive. The inhibition of H2O2 and nitric oxide (NO) production reduced the cell death rate induced by Si + Ag treatment. Si eliminated the up-regulation of alternative pathway by Ag. These data suggest that ethylene plays an important role in Si function in plants. Without ethylene, Si not only failed to enhance plant resistance, but also elevated H2O2 generation and further induced cell death in tobacco BY-2 cells.

A peptide-based nanofibrous hydrogel as a promising DNA nanovector for optimizing the efficacy of HIV vaccine.

This report shows that a nanovector composed of peptide-based nanofibrous hydrogel can condense DNA to result in strong immune responses against HIV. This nanovector can strongly activate both humoral and cellular immune responses to a balanced level rarely reported in previous studies, which is crucial for HIV prevention and therapy. In addition, this nanovector shows good biosafety in vitro and in vivo. Detailed characterizations show that the nanofibrous structure of the hydrogel is critical for the dramatically improved immune responses compared to existing materials. This peptide-based nanofibrous hydrogel shows great potential for efficacious HIV DNA vaccines and can be potentially used for delivering other vaccines and drugs.

Cyclic GMP is involved in auxin signalling during Arabidopsis root growth and development.

The second messenger cyclic guanosine 3',5'-monophosphate (cGMP) plays an important role in plant development and responses to stress. Recent studies indicated that cGMP is a secondary signal generated in response to auxin stimulation. cGMP also mediates auxin-induced adventitious root formation in mung bean and gravitropic bending in soybean. Nonetheless, the mechanism of the participation of cGMP in auxin signalling to affect these growth and developmental processes is largely unknown. In this report we provide evidence that indole-3-acetic acid (IAA) induces cGMP accumulation in Arabidopsis roots through modulation of the guanylate cyclase activity. Application of 8-bromo-cGMP (a cell-permeable cGMP derivative) increases auxin-dependent lateral root formation, root hair development, primary root growth, and gene expression. In contrast, inhibitors of endogenous cGMP synthesis block these processes induced by auxin. Data also showed that 8-bromo-cGMP enhances auxin-induced degradation of Aux/IAA protein modulated by the SCF(TIR1) ubiquitin-proteasome pathway. Furthermore, it was found that 8-bromo-cGMP is unable to directly influence the auxin-dependent TIR1-Aux/IAA interaction as evidenced by pull-down and yeast two-hybrid assays. In addition, we provide evidence for cGMP-mediated modulation of auxin signalling through cGMP-dependent protein kinase (PKG). Our results suggest that cGMP acts as a mediator to participate in auxin signalling and may govern this process by PKG activity via its influence on auxin-regulated gene expression and auxin/IAA degradation.

Revitalizing liver function in mice with liver failure through transplantation of 3D-bioprinted liver with expanded primary hepatocytes.

The utilization of three-dimensional (3D) bioprinting technology to create a transplantable bioartificial liver emerges as a promising remedy for the scarcity of liver donors. This study outlines our strategy for constructing a 3D-bioprinted liver, using in vitro-expanded primary hepatocytes recognized for their safety and enhanced functional robustness as hepatic cell sources for bioartificial liver construction. In addition, we have developed bioink biomaterials with mechanical and rheological properties, as well as printing capabilities, tailored for 3D bioprinting. Upon heterotopic transplantation into the mesentery of tyrosinemia or 90% hepatectomy mice, our 3D-bioprinted liver effectively restored lost liver functions, consequently extending the life span of mice afflicted with liver injuries. Notably, the inclusion of an artificial blood vessel in our 3D-bioprinted liver allowed for biomolecule exchange with host blood vessels, demonstrating, in principle, the rapid integration of the bioartificial liver into the host vascular system. This model underscores the therapeutic potential of transplantation for the treatment of liver failure diseases.

Rapid Self-Assembly Mini-Livers Protect Mice Against Severe Hepatectomy-Induced Liver Failure.

The construction of bioartificial livers, such as liver organoids, offers significant promise for disease modeling, drug development, and regenerative medicine. However, existing methods for generating liver organoids have limitations, including lengthy and complex processes (taking 6-8 weeks or longer), safety concerns associated with pluripotency, limited functionality of pluripotent stem cell-derived hepatocytes, and small, highly variable sizes (typically ≈50-500 µm in diameter). Prolonged culture also leads to the formation of necrotic cores, further restricting size and function. In this study, a straightforward and time-efficient approach is developed for creating rapid self-assembly mini-livers (RSALs) within 12 h. Additionally, primary hepatocytes are significantly expanded in vitro for use as seeding cells. RSALs exhibit consistent larger sizes (5.5 mm in diameter), improved cell viability (99%), and enhanced liver functionality. Notably, RSALs are functionally vascularized within 2 weeks post-transplantation into the mesentery of mice. These authentic hepatocyte-based RSALs effectively protect mice from 90%-hepatectomy-induced liver failure, demonstrating the potential of bioartificial liver-based therapy.

The correlation between early net fluid balance and the clinical outcomes of patients receiving extracorporeal cardiopulmonary resuscitation.

OBJECTIVE: To investigate correlation between early net fluid balance and the clinical outcomes of patients receiving extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: Adult patients on ECPR admitted to the Department of Emergency in the First Affiliated Hospital of Nanjing Medical University from May 2015 to December 2020 were included. Net fluid balance for consecutive 4 days after ECPR was recorded. The primary outcome was survival to intensive care unit (ICU) discharge. We used multivariable logistic regression to assess the association between fluid status and clinical outcomes. RESULTS: A total of 72 patients were enrolled and divided into two groups: the survivor group and the non-survivor group. The overall rate of survival to ICU discharge was 44.4%. Daily fluid balance (DFB) in the survivor group was lower than that in the non-survivor group at day 4 (-11.47 (-19.74, 8.7) vs. -5.08 (-12.94, 13.9) mL/kg, P=0.046), as was cumulative fluid balance (CFB) over the first 4 days (-36.03 (-51.45, 19.03) vs. -7.22 (-32.79, 21.02) mL/kg, P=0.009). Both continuous renal replacement therapy (CRRT) and CFB from days 1-4 were significantly correlated with survival to ICU discharge (OR=14.617, 95% CI: 1.344, 48.847, P=0.028; OR=1.261, 95% CI: 1.091, 1.375, P=0.003, respectively). CFB from days 1-4 was determined to have a roughly linear association with the log odds of survival to ICU discharge. CONCLUSION: Early negative fluid balance maybe associated with survival to ICU discharge in patients receiving ECPR.

Secondhand smoke, genetic susceptibility, and incident chronic kidney disease in never smokers: A prospective study of a selected population from the UK Biobank.

INTRODUCTION: A large number of people around the world are exposed to the risks of passive smoking. This prospective study aimed to examine the association between secondhand smoke exposure, exposure time, and the incidence of chronic kidney disease (CKD) and determine whether this association was influenced by genetic susceptibility. METHODS: The study included 214244 participants of the UK Biobank who were initially free of CKD. Cox proportional hazards model was used to estimate the associations between secondhand smoke exposure time and the risks of CKD in people who have never smoked. The genetic risk score for CKD was calculated by a weighted method. The likelihood ratio test comparing models was used to examine the cross-product term between secondhand smoke exposure and genetic susceptibility to CKD outcomes. RESULTS: During a median of 11.9 years of follow-up, 6583 incidents of CKD were documented. Secondhand smoke exposure increased the risk of CKD (HR=1.09; 95% CI: 1.03-1.16, p<0.01), and a dose-response relationship between CKD prevalence and secondhand smoke exposure time was found (p for trend<0.01). Secondhand smoke exposure increases the risk of CKD even in people who never smoke and have a low genetic risk (HR=1.13; 95% CI: 1.02-1.26, p=0.02). There was no statistically significant interaction between secondhand smoke exposure and genetic susceptibility to CKD (p for interaction=0.80). CONCLUSIONS: Secondhand smoke exposure is associated with higher risk of CKD, even in people with low genetic risk, and the relationship is dose dependent. These findings change the belief that people with low genetic susceptibility and without direct participation in smoking activities are not prone to CKD, emphasizing the need to avoid the harm of secondhand smoke in public places.

Risky working conditions and chronic kidney disease.

BACKGROUND: Individuals in the workplace are exposed to various environments, tasks, and schedules. Previous studies have indicated a link between occupational exposures and an increased risk of chronic kidney disease (CKD). However, the social conditions of the work environment may also be a crucial contributing factor to CKD. Furthermore, individuals may encounter multiple occupational-related risk factors simultaneously, underscoring the importance of investigating the joint risk of different working conditions on CKD. METHODS: A prospective analysis of 65,069 UK Biobank participants aged 40 to 69 years without CKD at baseline (2006-2010) was performed. A self-administered questionnaire assessed working conditions and a working conditions risk score were developed. Participants who answered "sometimes" or "often" exposure to occupational heat or occupational secondhand cigarette smoke; involved in shift work or heavy workloads ("usually" or "always"), were grouped as high-risk working conditions. Each working condition was scored as 1 if grouped as high-risk, and 0 if not. The working conditions risk score was equal to the sum of these four working conditions. Cox proportional hazard regression models were used to estimate the associations between working conditions and CKD incidence. RESULTS: The mean follow-up time was 6.7 years. After adjusting for demographic, lifestyle, and working time factors, the hazard ratios for the development of CKD for heavy workloads, shift work, occupational secondhand cigarette smoke exposure, and occupational heat exposure were 1.24 (95%CI = 1.03, 1.51), 1.33 (95%CI = 1.10, 1.62), 1.13 (95%CI = 1.01, 1.26), 1.11 (95%CI = 0.99, 1.24), respectively. The risk of CKD was found to be significantly associated with an increasing working conditions risk score. Individuals with a working conditions risk score of 4 had an 88.0% (95% CI = 1.05, 3.35) higher risk of developing CKD when compared to those with a working conditions risk score of 0. CONCLUSIONS: Adverse working conditions, particularly when considered in combination, can significantly elevate the risk of chronic kidney disease (CKD). These results provide a reference for implementing measures to prevent CKD.

Involvement of COP1 in ethylene- and light-regulated hypocotyl elongation.

Ethylene and light act through specific signal transduction mechanisms to coordinate the development of higher plants. Application of 1-aminocyclopropane-1-carboxylic acid (ACC, an ethylene precursor) suppresses the hypocotyl elongation of Arabidopsis seedlings in dark, but stimulates it in light. However, the mechanisms of opposite effects of ethylene on hypocotyl elongation in light and dark remain unclear. In the present study, we investigated the key factors involved in the opposite effects of ethylene on hypocotyl elongation in Arabidopsis seedlings. The effects of ACC on hypocotyl elongation of IAA-insensitive mutants including tir1-1, axr1-3, and axr1-12 seedlings were reduced in light but not in dark. The DR5 promoter, a synthetic auxin-response promoter, was used to quantify the level of IAA responses. There was a marked increase in DR5-GFP signals in response to ACC treatment in hypocotyls of DR5-GFP seedlings in light, but not in dark. CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) is an important downstream component of light signaling. ETHYLENE-INSENSITIVE3 (EIN3, an ethylene-stabilized transcription factor) directly regulates ETHYLENE-RESPONSE-FACTOR1 (ERF1). The cop1-4 mutant treated with ACC and cop1-4/EIN3ox plants developed long hypocotyls in darkness. Expression of ERF1 in the cop1-4 mutant was induced by ACC treatment in dark, but the expression of ERF1 in the wild type was not affected. Taken together, ethylene-promoting hypocotyl via IAA is mediated by light, and COP1 has a significant impact on the transcription of some genes downstream of EIN3. Thus, COP1 plays a crucial role in the opposite effects of ethylene on hypocotyl elongation.

Narciclasine inhibits the responses of Arabidopsis roots to auxin.

The plant hormone auxin plays a central role in the regulation of plant growth and development, as well as in responses to environmental stimuli. Narciclasine (NCS, an Amaryllidaceae alkaloid) isolated from Narcissus tazetta bulbs has a broad range of inhibitory effects on plants. In this study, the role of NCS in responses to auxin in Arabidopsis thaliana roots was investigated. We demonstrated the inhibitory effects of NCS on auxin-inducible lateral root formation, root hair formation, primary root growth, and the expression of primary auxin-inducible genes in Arabidopsis roots using DR5::GUS reporter gene, native auxin promoters (IAA12::GUS, IAA13::GUS), and quantitative reverse transcription PCR analysis. Results also showed that NCS did not affect the expression of cytokinin-inducible ARR5::GUS reporter gene. NCS relieved the auxin-enhanced degradation of the Aux/IAA repressor modulated by the SCFTIR1 ubiquitin-proteasome pathway. In addition, NCS did not alter the auxin-stimulated interaction between IAA7/AXR2 (Aux/IAA proteins) and the F-box protein TIR1 activity of the proteasome. Taken together, these results suggest that NCS acts on the auxin signaling pathway upstream of TIR1, which modulates Aux/IAA protein degradation, and thereby affects the auxin-mediated responses in Arabidopsis roots.

Synthesis and antibacterial activity evaluation of N (7) position-modified balofloxacins.

A series of small-molecule fluoroquinolones were synthesized, characterized by HRMS and NMR spectroscopy, and screened for their antibacterial activity against MRSA, P. aeruginosa, and E. coli as model G+/G- pathogens. Compounds 2-e, 3-e, and 4-e were more potent than the reference drug balofloxacin against MRSA and P. aeruginosa (MIC values of 0.0195 and 0.039 µg/ml for 2-e, 0.039 and 0.078 µg/ml for each of 3-e and 4-e, respectively). Analysis of the time-dependent antibacterial effect of compound 2-e toward MRSA showed that in the early logarithmic growth phase, bactericidal effects occurred, while in the late logarithmic growth phase, bacterial inhibition occurred because of concentration effects and possibly the development of drug resistance. Compound 2-e exhibited low toxicity toward normal mammalian cell lines 3T3 and L-02 and tumor cell lines A549, H520, BEL-7402, and MCF-7. The compound was not hemolytic. Atomic force microscopy (AFM) revealed that compound 2-e could effectively destroy the membrane and wall of MRSA cells, resulting in the outflow of the cellular contents. Docking studies indicated the good binding profile of these compounds toward DNA gyrase and topoisomerase IV. ADMET's prediction showed that most of the synthesized compounds followed Lipinski's "rule of five" and possessed good drug-like properties. Our data suggested that compound 2-e exhibited potent anti-MRSA activity and is worthy of further investigation.

Microbacterium kunmingensis sp. nov., an attached bacterium of Microcystis aeruginosa.

A Gram-stain positive, aerobic, rod-shaped actinobacterial strain designated as JXJ CY 27-2T was isolated from the culture of Microcystis aeruginosa FACHB-905 (Maf) collected from Lake Kunming, southwest China. The isolate was catalase positive, oxidase negative, and able to grow at 10.0-44.0 °C, pH 5.0-10.0 and 0-5.0% NaCl. Based on the 16S rRNA gene sequences, JXJ CY 27-2T showed high similarities of 98.54-98.55% with Microbacterium invictum DSM 19600T, Microbacterium saccharophilum DSM 28107T, and Microbacterium aoyamense DSM 19461T, and less than 98.47% similarities with other members of the genus. Its major cellular fatty acids were anteiso-C17:0 and anteiso-C15:0. The predominant menaquinones were MK-11 and MK-12. The diagnostic diamino acid in the cell wall peptidoglycan was lysine. Whole cell sugars contained mannose, ribose, galactose, rhamnose and arabinose. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, two unidentified glycolipids, and an unidentified lipid. The DNA G + C content was 69.8%. The digital DNA-DNA hybridization and average nucleotide identity values between strain JXJ CY 27-2T and its three closest similar strains were 18.4-20.3% and 74.9-75.7%, respectively. Based on the above data, strain JXJ CY 27-2T was identified as a new species of the genus Microbacterium, for which the name Microbacterium kunmingensis sp. nov. is proposed. The type strain is JXJ CY 27-2T (=CGMCC 1.17506T = KCTC 49382T). Strain JXJ CY 27-2T could promote the growth of Maf by providing it with available phosphorus, nitrogen and probably other nutrients such as vitamins and indole-3-acetate.

Renal fat fraction is significantly associated with the risk of chronic kidney disease in patients with type 2 diabetes.

Backgrounds: Ectopic fat deposition is closely related to chronic kidney disease (CKD). Currently, there are few population studies that have been conducted to determine the relationship between renal parenchyma fat deposition and the risk of CKD among patients with type 2 diabetes mellitus (T2DM). Therefore, we employed magnetic resonance imaging (MRI) to detect renal parenchyma fat content in individuals with T2DM, expressed as renal fat fraction (FF), to explore whether renal FF is an important risk factor for CKD in patients with T2DM. Methods: In this cross-sectional study, 189 subjects with T2DM were enrolled. CKD was defined as the estimated glomerular filtration rate (eGFR)<60 mL/min/1.73m2. Measurement of the renal FF was performed on a 3.0-T MRI (MAGNETOM Skyra, Siemens, Erlangen, Germany). Binary logistic regression was used to determine the association between tertiles of renal FF and risk of CKD. Receiver-operator characteristic (ROC) curves were constructed to evaluate the sensitivity and specificity of renal FF in detecting CKD in T2DM patients. Results: The patients were divided into three groups according to tertiles of the renal FF level (2.498 - 7.434). As renal FF increases, patients tend to be older, and more abdominally obese, with a decreased eGFR (p<0.05). After adjustment for potential confounders, patients in the highest tertile of renal FF had a significantly increased risk of CKD than those in the lowest tertile (odds ratio (OR) = 3.98, 95% confidence interval (CI) = 1.12 - 14.09, p = 0.032), and the area under the ROC curve for this model was 0.836 (0.765-0.907). Conclusions: The renal FF is significantly independently associated with CKD in patients with T2DM.

PIM1 promotes hepatic conversion by suppressing reprogramming-induced ferroptosis and cell cycle arrest.

Protein kinase-mediated phosphorylation plays a critical role in many biological processes. However, the identification of key regulatory kinases is still a great challenge. Here, we develop a trans-omics-based method, central kinase inference, to predict potentially key kinases by integrating quantitative transcriptomic and phosphoproteomic data. Using known kinases associated with anti-cancer drug resistance, the accuracy of our method denoted by the area under the curve is 5.2% to 29.5% higher than Kinase-Substrate Enrichment Analysis. We further use this method to analyze trans-omic data in hepatocyte maturation and hepatic reprogramming of human dermal fibroblasts, uncovering 5 kinases as regulators in the two processes. Further experiments reveal that a serine/threonine kinase, PIM1, promotes hepatic conversion and protects human dermal fibroblasts from reprogramming-induced ferroptosis and cell cycle arrest. This study not only reveals new regulatory kinases, but also provides a helpful method that might be extended to predict central kinases involved in other biological processes.

Kinsenoside alleviates inflammation and fibrosis in experimental NASH mice by suppressing the NF-κB/NLRP3 signaling pathway.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) has replaced viral hepatitis as the main driver of the rising morbidity and mortality associated with cirrhosis and liver cancer worldwide, while no FDA-approved therapies are currently known. Kinsenoside (KD), naturally isolated from Anoectochilus roxburghii, possesses multiple biological activities, including lipolysis, anti-inflammation, and hepatoprotection. However, the effects of KD on NASH remain unclear. PURPOSE: This study aimed to explore the roles of KD in NASH and its engaged mechanisms. METHODS: Two typical animal models of NASH, mice fed a methionine-choline-deficient (MCD) diet (representing non-obese NASH) and mice fed a high-fat and -fructose diet (HFFD) (representing obese NASH), were used to investigate the effect of KD on NASH in vivo. Transcriptome sequencing was performed to elucidate the underlying mechanisms of KD. Lipopolysaccharide (LPS)-stimulated THP-1 cells and transforming growth factor ß1 (TGF-ß1)-activated LX-2 cells were applied to further explore the effects and mechanisms of KD in vitro. RESULTS: The intragastric administration of KD remarkably alleviated MCD/HFFD-induced murine NASH almost in a dose-dependent manner. Specifically, KD reduced lipid accumulation, inflammation, and fibrosis in the liver of NASH mice. KD ameliorated alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), and malondialdehyde (MDA) abnormalities. In addition, it decreased the level of serum proinflammatory factors (IL-12p70, IL-6, TNF-α, MCP-1, IFN-γ) and the hepatic expression of typical fibrosis-related molecules (α-SMA, Col-I, TIMP-1). Mechanically, KD attenuated the MCD/HFFD-induced NASH through the inhibition of the NF-κB/NLRP3 signaling pathway. Consistently, KD reduced inflammation stimulated by LPS in THP-1 cells via suppressing the NF-κB/NLRP3 pathway. Furthermore, it prevented the activation of LX-2 cells directly, by inhibiting the proliferation stimulated by TGF-ß1, and indirectly, by inactivating the NLRP3 inflammasome in macrophages. CONCLUSION: For the first time, the practical improvement of NASH by KD was revealed. Our study found that KD exerted its alleviative effects on NASH through the inhibition of the NF-κB/NLRP3 signaling pathway. Given its hepatoprotective and nontoxic properties, KD has the potential to be a novel and effective drug to treat NASH.